Variant 4-25003474-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018176.4(LGI2):c.1615A>G(p.Ile539Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,595,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

LGI2
NM_018176.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.27

Variant links:

Genes affected

LGI2 (HGNC:18710): (leucine rich repeat LGI family member 2) Predicted to be involved in inhibitory synapse assembly. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

LGI2 links:

LOC102723675 (HGNC:):

LOC102723675 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.026076555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LGI2	NM_018176.4 linkuse as main transcript	c.1615A>G	p.Ile539Val	missense_variant	8/8	ENST00000382114.9	NP_060646.2
LOC102723675	XR_001741618.3 linkuse as main transcript	n.7860T>C		non_coding_transcript_exon_variant	4/4
LGI2	XM_017008356.2 linkuse as main transcript	c.820+8861A>G		intron_variant			XP_016863845.1
LOC102723675	XR_007058082.1 linkuse as main transcript	n.1048+6933T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LGI2	ENST00000382114.9 linkuse as main transcript	c.1615A>G	p.Ile539Val	missense_variant	8/8	1	NM_018176.4	ENSP00000371548	P1
LGI2	ENST00000512108.1 linkuse as main transcript	c.628-3568A>G		intron_variant		2		ENSP00000426254

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000107

AC:

AN:

234688

Hom.:

AF XY:

0.000134

AC XY:

AN XY:

126962

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000994

Gnomad NFE exome

AF:

0.0000274

Gnomad OTH exome

AF:

0.000178

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1442808

Hom.:

Cov.:

AF XY:

0.0000460

AC XY:

AN XY:

716952

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000365

Gnomad4 FIN exome

AF:

0.00102

Gnomad4 NFE exome

AF:

0.00000543

Gnomad4 OTH exome

AF:

0.000202

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000952

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2024

The c.1615A>G (p.I539V) alteration is located in exon 8 (coding exon 8) of the LGI2 gene. This alteration results from a A to G substitution at nucleotide position 1615, causing the isoleucine (I) at amino acid position 539 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.55

DEOGEN2

Benign

0.024

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.78

M_CAP

Benign

0.0092

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.24

REVEL

Benign

0.16

Sift

Benign

1.0

Sift4G

Benign

0.83

Polyphen

0.0010

Vest4

0.068

MVP

0.45

MPC

0.40

ClinPred

0.028

GERP RS

5.6

Varity_R

0.045

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over